Pharmaceuticals

Editorial

Jump to: Research, Review

4 pages, 204 KiB

Open AccessEditorial

Novel Approaches for Targeting Metalloproteinases

by Salvatore Santamaria

Pharmaceuticals 2023, 16(12), 1637; https://doi.org/10.3390/ph16121637 - 22 Nov 2023

Viewed by 1011

Abstract

With 187 genes, metalloproteinases represent the most abundant protease family in the human proteome [...] Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

Research

Jump to: Editorial, Review

16 pages, 3456 KiB

Open AccessArticle

Obeticholic Acid Reduces Kidney Matrix Metalloproteinase Activation Following Partial Hepatic Ischemia/Reperfusion Injury in Rats

by Giuseppina Palladini, Marta Cagna, Laura Giuseppina Di Pasqua, Luciano Adorini, Anna Cleta Croce, Stefano Perlini, Andrea Ferrigno, Clarissa Berardo and Mariapia Vairetti

Pharmaceuticals 2022, 15(5), 524; https://doi.org/10.3390/ph15050524 - 24 Apr 2022

Cited by 4 | Viewed by 2626

Abstract

We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The present study investigated the capacity of OCA to modulate [...] Read more.

We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The present study investigated the capacity of OCA to modulate MMPs in distant organs such as the kidney. Male Wistar rats were dosed orally with 10 mg/kg/day of OCA (5 days) and were subjected to 60-min partial hepatic ischemia. After 120-min reperfusion, kidney biopsies (cortex and medulla) and blood samples were collected. Serum creatinine, kidney MMP-2, and MMP-9-dimer, tissue inhibitors of MMPs (TIMP-1, TIMP-2), RECK, TNF-alpha, and IL-6 were monitored. MMP-9-dimer activity in the kidney cortex and medulla increased after hepatic I/R and a reduction was detected in OCA-treated I/R rats. Although not significantly, MMP-2 activity decreased in the cortex of OCA-treated I/R rats. TIMPs and RECK levels showed no significant differences among all groups considered. Serum creatinine increased after I/R and a reduction was detected in OCA-treated I/R rats. The same trend occurred for tissue TNF-alpha and IL-6. Although the underlying mechanisms need further investigation, this is the first study showing, in the kidney, beneficial effects of OCA by reducing TNF-alpha-mediated expression of MMPs after liver I/R. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Graphical abstract

15 pages, 2331 KiB

Open AccessArticle

Matrix Metalloproteinase-2 Inhibition in Acute Ischemia-Reperfusion Heart Injury—Cardioprotective Properties of Carvedilol

by Monika Skrzypiec-Spring, Joanna Urbaniak, Agnieszka Sapa-Wojciechowska, Jadwiga Pietkiewicz, Alina Orda, Bożena Karolko, Regina Danielewicz, Iwona Bil-Lula, Mieczysław Woźniak, Richard Schulz and Adam Szeląg

Pharmaceuticals 2021, 14(12), 1276; https://doi.org/10.3390/ph14121276 - 7 Dec 2021

Cited by 9 | Viewed by 2592

Abstract

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect [...] Read more.

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect against cardiac contractile dysfunction related with IR injury. Isolated rat hearts were subjected to either control aerobic perfusion or IR injury: 25 min of aerobic perfusion, followed by 20 min global, no-flow ischemia, and reperfusion for 30 min. The effects of carvedilol, nebivolol, or metoprolol were evaluated in hearts subjected to IR injury. Cardiac mechanical function and MMP-2 activity in the heart homogenates and coronary effluent were assessed along with troponin I content in the former. Only carvedilol improved the recovery of mechanical function at the end of reperfusion compared to IR injury hearts. IR injury induced the activation and release of MMP-2 into the coronary effluent during reperfusion. MMP-2 activity in the coronary effluent increased in the IR injury group and this was prevented by carvedilol. Troponin I levels decreased by 73% in IR hearts and this was abolished by carvedilol. Conclusions: These data suggest that the cardioprotective effect of carvedilol in myocardial IR injury may be mediated by inhibiting MMP-2 activation. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

19 pages, 4112 KiB

Open AccessArticle

Coumarin Derivatives Act as Novel Inhibitors of Human Dipeptidyl Peptidase III: Combined In Vitro and In Silico Study

by Dejan Agić, Maja Karnaš, Domagoj Šubarić, Melita Lončarić, Sanja Tomić, Zrinka Karačić, Drago Bešlo, Vesna Rastija, Maja Molnar, Boris M. Popović and Miroslav Lisjak

Pharmaceuticals 2021, 14(6), 540; https://doi.org/10.3390/ph14060540 - 5 Jun 2021

Cited by 10 | Viewed by 3500

Abstract

Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is a member of the metalloproteinase family M49 with distribution detected in almost all forms of life. Although the physiological role of human DPP III (hDPP III) is not yet fully elucidated, its involvement in [...] Read more.

Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is a member of the metalloproteinase family M49 with distribution detected in almost all forms of life. Although the physiological role of human DPP III (hDPP III) is not yet fully elucidated, its involvement in pathophysiological processes such as mammalian pain modulation, blood pressure regulation, and cancer processes, underscores the need to find new hDPP III inhibitors. In this research, five series of structurally different coumarin derivatives were studied to provide a relationship between their inhibitory profile toward hDPP III combining an in vitro assay with an in silico molecular modeling study. The experimental results showed that 26 of the 40 tested compounds exhibited hDPP III inhibitory activity at a concentration of 10 µM. Compound 12 (3-benzoyl-7-hydroxy-2H-chromen-2-one) proved to be the most potent inhibitor with IC₅₀ value of 1.10 μM. QSAR modeling indicates that the presence of larger substituents with double and triple bonds and aromatic hydroxyl groups on coumarin derivatives increases their inhibitory activity. Docking predicts that 12 binds to the region of inter-domain cleft of hDPP III while binding mode analysis obtained by MD simulations revealed the importance of 7-OH group on the coumarin core as well as enzyme residues Ile315, Ser317, Glu329, Phe381, Pro387, and Ile390 for the mechanism of the binding pattern and compound 12 stabilization. The present investigation, for the first time, provides an insight into the inhibitory effect of coumarin derivatives on this human metalloproteinase. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Graphical abstract

18 pages, 7453 KiB

Open AccessArticle

Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

by Shurong Hou, Juan Diez, Chao Wang, Christoph Becker-Pauly, Gregg B. Fields, Thomas Bannister, Timothy P. Spicer, Louis D. Scampavia and Dmitriy Minond

Pharmaceuticals 2021, 14(3), 203; https://doi.org/10.3390/ph14030203 - 28 Feb 2021

Cited by 7 | Viewed by 3122

Abstract

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous [...] Read more.

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

17 pages, 3815 KiB

Open AccessArticle

Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

by Chao Wang, Juan Diez, Hajeung Park, Christoph Becker-Pauly, Gregg B. Fields, Timothy P. Spicer, Louis D. Scampavia, Dmitriy Minond and Thomas D. Bannister

Pharmaceuticals 2021, 14(3), 197; https://doi.org/10.3390/ph14030197 - 27 Feb 2021

Cited by 5 | Viewed by 3073

Abstract

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other [...] Read more.

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). Here, in part II, we report further efforts to optimize potency and selectivity. We hope that a hydroxamic acid meprin α inhibitor probe will help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

14 pages, 1998 KiB

Open AccessCommunication

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

by Antonio Laghezza, Luca Piemontese, Leonardo Brunetti, Alessia Caradonna, Mariangela Agamennone, Fulvio Loiodice and Paolo Tortorella

Pharmaceuticals 2021, 14(2), 85; https://doi.org/10.3390/ph14020085 - 24 Jan 2021

Cited by 2 | Viewed by 2104

Abstract

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, [...] Read more.

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

17 pages, 1146 KiB

Open AccessReview

Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure

by Pricila Rodrigues Gonçalves, Lisandra Duarte Nascimento, Raquel Fernanda Gerlach, Keuri Eleutério Rodrigues and Alejandro Ferraz Prado

Pharmaceuticals 2022, 15(8), 920; https://doi.org/10.3390/ph15080920 - 25 Jul 2022

Cited by 38 | Viewed by 3754

Abstract

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in [...] Read more.

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Graphical abstract

19 pages, 393 KiB

Open AccessReview

Targeting Cartilage Degradation in Osteoarthritis

by Oliver McClurg, Ryan Tinson and Linda Troeberg

Pharmaceuticals 2021, 14(2), 126; https://doi.org/10.3390/ph14020126 - 5 Feb 2021

Cited by 26 | Viewed by 5175

Abstract

Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated [...] Read more.

Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along with recent clinical trials on FGF18 and Wnt pathway inhibitors. We also considered dendrimer-based approaches being developed to deliver and retain such therapeutics in the joint environment. These may reduce systemic side effects while improving local half-life and concentration. Development of such targeted anabolic therapies would be of great benefit in the osteoarthritis field. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Graphical abstract

25 pages, 6014 KiB

Open AccessReview

Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer’s Disease

by Lidia Ciccone, Jennifer Vandooren, Susanna Nencetti and Elisabetta Orlandini

Pharmaceuticals 2021, 14(2), 86; https://doi.org/10.3390/ph14020086 - 24 Jan 2021

Cited by 33 | Viewed by 4592

Abstract

Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated [...] Read more.

Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer’s disease. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

17 pages, 1748 KiB

Open AccessReview

The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors

by Nabangshu Das, Colette Benko, Sean E. Gill and Antoine Dufour

Pharmaceuticals 2021, 14(1), 31; https://doi.org/10.3390/ph14010031 - 31 Dec 2020

Cited by 15 | Viewed by 4659

Abstract

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat^®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on [...] Read more.

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat^®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Figure 1

21 pages, 4302 KiB

Open AccessFeature PaperReview

Developments in Carbohydrate-Based Metzincin Inhibitors

by Doretta Cuffaro, Elisa Nuti, Felicia D’Andrea and Armando Rossello

Pharmaceuticals 2020, 13(11), 376; https://doi.org/10.3390/ph13110376 - 10 Nov 2020

Cited by 4 | Viewed by 2857

Abstract

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small [...] Read more.

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models. Full article

(This article belongs to the Special Issue Novel Approaches for Targeting Metalloproteinases)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Novel Approaches for Targeting Metalloproteinases

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (12 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI